Bipolar disorder is one of the most important causes of disability in people between the ages of 15 and 44. It is characterised by recurrent episodes of mania or elevated mood, and irritable or depressive moods. It is distinct from other mood disorders, for example depressive illnesses such as depression or recurrent depression, manic disorders such as mania or hypomania, or persistent mood disorders such as cyclothymia and dysthymia, being separately classified in the World Health Organisation's International Statistical Classification of Diseases and Related Health Problems.
Present treatments include valproic acid, lamotrigine, carbamazepine and lithium in the form of salts such as lithium carbonate or lithium citrate. Although generally considered to be the most effective treatment, lithium suffers from the problem of toxicity, its toxic level being only twice that of its therapeutic concentration. It can also cause side effects such as polyurea, polydypsia, and kidney damage, in addition to interfering with glucose metabolism.
It is believed that the ability to inhibit the enzyme inositol monophosphatase (IMPase) is a key factor in the control of bipolar disorder. IMPase catalyses the hydrolysis of inositol monophosphate (IP1) to inositol, and is required for regeneration of membrane phospholipids having an inositol head group. Hydrolysis of the head group of the phospholipid inositol 4,5-bisphosphate (PIP2) releases inositol 1,4,5-triphosphate (IP3) and diacyl glycerol (DAG). IP3 diffuses into the cytosol, and opens calcium channels to increase calcium. DAG stays in the membrane and activates protein kinase C. The enzyme phospholipase C (PLC) catalysis the hydrolysis of PIP2, and is under hormonal and neurotransmitter control. It is thought that inhibiting these signalling cascades in the phosphoinositide pathway (PI) is why lithium helps in bipolar disorder, by controlling certain populations of neurons which are overactive. This is illustrated in FIG. 1.
Berridge et al, in Cell, 59, 411-419, 1989, suggest that IMPase inhibition is the most plausible reason why lithium is successful in treating bipolar disorder. In WO 2009/138987, it was suggested that a dodecapeptide that had demonstrable IMPase inhibition activity could have potential utility in treating mood disorders. Additionally, WO96/37197 describes the use of tropolone derivatives as inhibitors of IMPase, and also their potential use in the treatment of mania and depression. Giocebbe et al in U.S. Pat. No. 4,981,980 further report that fermentation of a nutrient medium by a hypomycetes fungus of the genus Memnoniella or Stachybotrys yields a product, the major component of which can inhibit inositol monophosphatase, and is useful in the treatment of manic depression.
Atack et al, in Medicinal Research Reviews, 17(2), 1997, pp 215-224, proposed that the side-effects of lithium could be associated with its non-specificity to the IMPase enzyme, and attempted to develop new, specific inhibitors of IMPase based on analogues of the substrate, inositol. However, the compounds prepared either suffered from poor inhibition, or from poor bio-permeability.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is a known compound that has antioxidant activity (Muller et al; Biochemical Pharmacology, 33(20), 3235-3239, 1984), and has also been reported as being active in treating a number of therapeutic indications, for example as an antidepressant (Posser et al; European Journal of Pharmacology, 602, 85-91, 2009), for prevention and treatment of infectious diseases, for treatment of malignant tumours, for stimulating the immune system, for treating selenium deficiency diseases, for anti-arteriosclerotic and anti-inflammatory treatments (U.S. Pat. No. 5,021,242), in treating side-effects caused by medical use of cisplatin (WO92/02221), in treating noise-induced hearing loss (Lynch et al, Seminars in Hearing, 30(1), 47-55, 2009) and in treating mental illnesses that are treatable by promoting release of zinc from metallothionein, such as depression and schizophrenia (WO 99/49680). Its use in the treatment of cancer is also reported in US 2006/211745. It has been evaluated in phase III clinical trials for other disorders such as stroke and atherosclerosis, and is thus believed to be safe for use in humans.
None of these documents report the capability of ebselen, or analogues thereof, to act as an inhibitor of IMPase, and hence do not teach or disclose the use of ebselen or analogues thereof in treating conditions that are treatable through inhibition of the IMPase enzyme, such as bipolar disorder.